This invention relates generally to radioactive compounds which are useful as radiopharmaceuticals, and more particularly, to radioiodinated benzovesamicol analogs which selectively localize in presynaptic cholinergic neurons.
Alzheimer's disease, which is often characterized by the degeneration of the cholinergic nerves, is increasingly prevalent as the mean age of the American population increases. It has been estimated that there are approximately between 5 and 6 million persons in the United States afflicted with Alzheimer's disease.
It would be highly desirable to be able to image cholinergic nerves to assess the extent and regional pattern of nerve damage in Alzheimer patients. Moreover, such brain imaging would be useful for diagnosing and monitoring patients with rarer neurological disorders, such as olivopontocerebellar atrophy, progressive supranuclear palsy, and patients demented by Parkinson's disease.
In the present state of the art, patients with Alzheimer's disease and related neurological disorders, are being imaged with radiopharmaceuticals which are indicators of brain blood flow or brain metabolism. Positron emission tomography (PET) studies have revealed that patients with clinically diagnosed Alzheimer's disease have reduced metabolism and perfusion, particularly in the posterior parietal and in the frontal regions of the brain. Moreover, PET studies have demonstrated that a significant increase in right/left metabolic asymmetry is associated with predominantly lateralized neuropsychological deficits.
Single photon emission computed tomography (SPECT) perfusion studies of regional blood flow have been done with a xenon-133 inhalation method and with intravenous administration of N-isopropyl-.sup.123 I iodoamphetamine. More recently, technetium-99m hexamethylpropylenamine oxime has been utilized as a tracer for SPECT studies inasmuch as it crosses the blood-brain barrier and is completely cleared from the blood in a single passage through the cerebral circulation so that regional distribution is proportionate to regional blood flow.
The known radiotracers for brain imaging are lipophilic, and therefore move across the blood-brain barrier with nearly complete extraction during a single pass through the cerebral circulation. Once inside, however, these radiotracers bind to nonspecific receptors, or are metabolized to non-lipophilic compounds. It is an unfortunate characteristic of these radiopharmaceuticals that they do not localize in the brain based on their affinity for presynaptic cholinergic neurons.
The most consistent and profound of the currently recognized changes in patients afflicted with Alzheimer's disease involves the acetylcholine-containing neurons projecting from the basal forebrain nuclei to cerebral cortex and other forebrain areas. Reductions in the activity of choline acetyltransferase, an enzyme marker for cholinergic neurons, appears to correlate best with the severity of cognitive deficits and neuropathologic alterations found in this disorder. There is, thus, a need for a marker of choline acetyltransferase activity.
Another imaging agent which has been employed to diagnose Alzheimer's disease with SPECT is .sup.123 I-labeled 3-quinuclidinyl-4-iodobenzilate. This radiopharmaceutical permits in vivo imaging of muscarinic acetylcholine receptor binding function. Alzheimer's disease patients exhibit an impairment of muscarinic receptor binding function relative to a normal age-matched subject. However, .sup.123 I-labeled 3-quinuclidinyl-4-iodobenzilate does not localize, or image, cholinergic neurons.
CAT scanning has been used to determine the size and location of brain tumors, and to determine the degree of brain atrophy that accompanies many neurological disorders. However, CAT scanning techniques are not capable of detecting primary deficits in the cholinergic neurons of the brain. Magnetic resonance imaging (MRI) is likewise deficient in its ability to detect deficits in the cholinergic neurons. There is, therefore, a need for a radiopharmaceutical which enables selective localization and imaging of cholinergic neurons.
Vesamicol, an acetylcholine-storage-blocking drug (available from Research Biochemicals Incorporated, Nattick, MA), is a potent inhibitor of the vesicular sequestration of acetylcholine. Vesamicol, which is chemically denominated trans-2-(4-phenylpiperidino)-cyclohexanol, exhibits enantioselectivity with (-)-vesamicol, which is 25 times more potent than (+)-vesamicol. ##STR2## Structural studies and kinetic data suggest that vesamicol binds to the outside of the storage vesicle membrane at a locus distinct from the active site of the acetylcholine transporter. The blocking activity of many analogs of vesamicol have been reported in Rogers, et al., J. Med. Chem., Vol. 32, No. 6, pp. 1217-1230 (1989). A number of derivatives in the benzovesamicol series are substantially equipotent to vesamicol. ##STR3##
Tritiated Vesamicol has been utilized as a probe for in vitro research on cholinergic neurons. While such radio-tagging does yield radio-emissive compounds, the emission is strictly of the weak .beta.-type, so that any intersecting structure, such as nearby tissue in vivo, may completely absorb, or substantially mask, the emission before the tritium can be detected. Therefore, .beta.-measuring instruments must be very sensitive and intervening tissue absorption must be factored in, thereby increasing the problems created by the use of .beta.-emissive radio-tagged Vesamicol in vivo and limiting its usage to laboratory situations. Thus, a radio-tagged form of Vesamicol having a stronger emissive character would be of substantial benefit to an investigator of the pharmacological actions of Vesamicol.
It is, therefore, an object of this invention to provide a gamma-emitting radiopharmaceutical which localizes selectively in vivo in brain cholinergic neurons.
It is another object of this invention to provide a gamma-emitting radiopharmaceutical for scintigraphic imaging using imaging devices presently found in most nuclear medicine or radiology clinics throughout the country.
It is also an object of this invention to provide a gamma-emitting radiopharmaceutical which can be easily labeled.
It is a further object of this invention to provide a gamma-emitting radiopharmaceutical which can be used to portray density and regional distribution of cholinergic nerves in the brain of patients afflicted with Alzheimer's disease and related neurological disorders.